Process and device for preparing radiopharmaceutical products for injection

ABSTRACT

Method for preparing, packaging and handling an individual dose of a radiopharmaceutical compound, comprising the following steps:  
     filling a cartridge ( 1 ) with said dose of radiopharmaceutical compound via a first end, the second end being closed by means of a component serving as a piston ( 3 );  
     closing said cartridge ( 1 ) at said first end by means of a closure device ( 2 );  
     placing said cartridge ( 1 ) in a radiation shielding device ( 10 ), comprising an inner part ( 4 ) and an outer part ( 5 ), said inner part serving as radiation shielding for an operator and said outer part serving as a transportation shielding container;  
     closing said container by means of an appropriate shielding lid ( 6 );  
     transporting said container up to the place at which an injection of said radiopharmaceutical compound will take place;  
     removing the shielding lid ( 6 ) of the container;  
     fixing a plunger ( 7 ) to the cartridge piston ( 3 );  
     extracting the cartridge and the inner part ( 4 ) of the radiation shielding device ( 10 ) from the outer part ( 5 ) serving as a container, and  
     placing injection means ( 30 ) on the cartridge end which has the setting closure device ( 2 ).

FIELD OF THE INVENTION

[0001] The present invention is related to practices in nuclearmedicine, and in particular to a process for preparingradiopharmaceutical products for injection.

STATE OF THE ART

[0002] The development of nuclear medicine, in particular in the fieldof diagnosis by positron emission tomography (PET), makes it necessaryto review the usual methods for producing, packaging and handlingradiopharmaceutical substances intended for administration to patients.

[0003] Radiopharmaceutical substances are chemical compounds labeledwith radioactive isotopes, intended for medical use. Problems ofexisting methods and equipment are mainly due to the increase in the useof isotopes whose radiation energy is relatively high, and by the factthat a higher level of automation is required due to the short half-lifeof said isotopes.

[0004] Dose fractionation systems are available on the market. They makeit possible to dilute a base radiopharmaceutical product, to prepare thedilute solution in vials and to place these vials in radiation shieldingfor transportation. The vials are then delivered to the nuclear medicinedepartments of hospitals. Such devices are mainly used byradiopharmaceutical production companies.

[0005] Vial di systems allow to provide radio-pharmaceutical in vialsaccording to the common practice in mos pean hospitals: the vials maycontain doses for several examinations or for several patients. Theinjection is prepared by the hospital staff: the doctor or a member ofhis specialist staff fills a syringe for each patient or for eachexamination from a “multi-dose” vial, that is to say a vial that maycontain enough substance for several examinations or for severalpatients. This handling exposes the hospital staff on a repeated basis,giving rise to an appreciable cumulative exposure. This dose isgenerally limited by performing the operation behind lead protectionsuch as a radiation-shielded glove box. The syringe may be fitted into asyringe radiation shielding.

[0006] The practice is different in the United States: hospitals receivethe syringes pre-filled with the individual “patient-dose”. The fillingof these syringes is carried out in “radiopharmacies” (this concept isnot widespread in Europe). This operation remains essentially manual: itis usually performed with handling tongs in radiation-shielded cells. Itis slow and labor-intensive. The syringes are then placed, with theirneedle and cap, in a radiation-shielded transportation container.

[0007] In the hospital, just before injection, the syringe is removedfrom its transportation radiation shielding container and generallyfitted into a syringe radiation shielding. This operation represents acertain level of exposure of the staff to the radiation.

[0008] It should be noted that automation of the filling of syringes ispossible and that such devices exist, but they do not solve all theproduction problems: the fixing of the needle or a stopper is notautomated, nor is the placing of the syringe in its transportationcontainer. For these reasons, they are not widely used.

[0009] It should be noted that if the needle for the injection isalready in place, as is generally the case, the syringe is not closedduring transportation. The integrity of the product is not ensuredduring the transportation. Alternatively, if the syringe is closed bymeans of a stopper, this stopper will have to be removed by the medicalstaff and replaced by the needle for the injection. This manipulationrepresents an exposure to radiation and presents a risk of radioactivecontamination of the staff, and also a risk of biological contaminationof the substance.

[0010] A multi-dose radiopharmaceutical vial dispensing device is oflittle interest to the American market since it does not allow theautomatic filling of individual patient-doses which may be used directlyin hospitals according to the common practice. In the long-term, thepractice of the individual patient-dose might spread beyond the UnitedStates on account of the ease offered to the hospital departmentsconcerned.

[0011] The problem present in the state of the art that need to besolved an be summarized as follows:

[0012] syringes are a form of packaging which does not lend itselfreadily automation. The design of a system for the automated filling ofsyringes, which would directly satisfy the need and habits of theAmerican market, would be complex;

[0013] the filling of a syringe as is currently performed in Americanradiopharmacies, in particular for PET applications, is essentiallymanual, slow and relatively inefficient;

[0014] Document U.S. Pat. No. 5,918,443 describes fluid leakproofpackage for a single-dose radiopharmaceutical-filled medical syringe.Said package is made of an inner container enclosing the completesyringe and which is in turn enclosed within a radiation-shielding outercontainer useful for shipment to a medical treatment location. Howeverthe configuration of this device implies that, before transportation,the syringe has to be filled and the needle capped manually, thusexposing the operator. Further, both above-mentioned containers have tobe capped and uncapped respectively. Only the outer container and itscap comprise radiation-shielding material. Thus the medical staffcarrying out on-site injection is further exposed during uncapping andduring injection. the fixing of the needle or a stopper is notautomated, nor is the placing of the syringe in its transportationcontainer. For these reasons, they are not widely used.

[0015] It should be noted that if the needle for the injection isalready in place, as is generally the case, the syringe is not closedduring transportation. The integrity of the product is not ensuredduring the transportation. Alternatively, if the syringe is closed bymeans of a stopper, this stopper will have to be removed by the medicalstaff and replaced by the needle for the injection. This manipulationrepresents an exposure to radiation and presents a risk of radioactivecontamination of the staff, and also a risk of biological contaminationof the substance.

[0016] A multi-dose radiopharmaceutical vial dispensing device is oflittle interest to the American market since it does not allow theautomatic filling of individual patient-doses which may be used directlyin hospitals according to the common practice. In the long-term, thepractice of the individual patient-dose might spread beyond the UnitedStates on account of the ease offered to the hospital departmentsconcerned.

[0017] The problems present in the state of the art that need to besolved can be summarized as follows:

[0018] syringes are a form of packaging which does not lend itselfreadily to automation. The design of a system for the automated fillingof syringes, which would directly satisfy the need and habits of theAmerican market, would be complex;

[0019] the filling of a syringe as is currently performed in Americanradiopharmacies, in particular for PET applications, is essentiallymanual, slow and relatively inefficient;

[0020] Document JP-A-02 095380 proposes a device to safely and surelytransport and store a radioactive solution. This device providesimprovements intended to reduce medical staff and operator exposure. Forinstance, for the needs of storage and transportation, only a sealedsyringe body is inserted into an inner first radiation-shieldingcontainer itself enclosed in an outer second radiation-shieldingcontainer, the latter being provided with a radiation-shielding lid. Thematerials used for the inner container are for example lead, tungstenalloy as well as lead glass in the case where a see-through window isprovided. The outer container comprises lead.

[0021] The syringe body is maintained in the device by means of a flangeand a collar which are attached to the rear of the syringe body insertedin the inner shielding container.

[0022] The advantage of this solution over the previous one is thatglobally the shielding device is much more compact and thus less heavy.At the injection location, a plunger rod, also made of tungsten alloy toprevent radiation leakage to the rear, is screwed into a sealing gasketlocated inside the syringe body. Thus the syringe inserted in the innershielding cylinder can be easily retrieved from the second shieldingcontainer.

[0023] A first drawback of this device is the need to manually remove asealing rubber stopper at the front face of the syringe in order toplace the needle, which leads to personal exposure and possiblesterility loss or biological contamination. Moreover the cantileveredgasket-plunger connection is weakened owing to the weight of shieldedparts. the fixing of the needle in a stopper is not automated, nor isthe placing of the syringe in its transportation container. For thesereasons, they are not widely used.

[0024] It should be noted that if the needle for the injection isalready in place, as is generally the case, the syringe is not closedduring transportation. The integrity of the products is not ensuredduring the transportation. Alternatively, the syringe is closed by meansof a stopper, this stopper will have to be removed by the medical staffand replaced by the needle for the injection. This manipulationrepresents an exposure to radiation and presents a risk of radioactivecontamination of the staff, and also a risk of biological contaminationof the substance.

[0025] A multi-dose radiopharmaceutical vial dispensing device is oflittle interest to the American market since it does not allow theautomatic filling of individual patient-doses which may be used directlyin hospitals according to the common practice. In the long-term, thepractice of the individual patient-dose might spread beyond the UnitedStates on account of the ease offered to the hospital departmentsconcerned.

[0026] The problems present in the state of the art that need to besolved can be summarized as follows:

[0027] syringes are a form of packaging which does not lend itselfreadily to automation. The design of a system for the automated fillingof syringes, which would directly satisfy the need and habits of theAmerican market, would be complex;

[0028] the filling of a syringe as is currently performed in Americanradiopharmacies, in particular for PET applications, is essentiallymanual, slow and relatively inefficient

[0029] Possible contamination or exposure of the radiopharmacies staffis thus a risk inherent to manual handling of syringes. Regarding this,automated filling is required. However usual syringes constitute a formof packaging which does not lend itself readily to automation. Thedesign of a system for the automated filling of syringes, which woulddirectly satisfy the need and habits of the American market, would becomplex;

[0030] the use of individual syringes does not entirely avoidmanipulations at the hospital since they must be transferred from theirtransportation radiation shielding container to the syringe radiationshielding;

[0031] pre-filled individual syringes, possibly comprising needle,syringe body and plunger, are very long and require large, and thusheavy, transportation radiation shielding containers;

[0032] when the syringes are delivered with a needle, the container(i.e. syringe) thus provided is open and the sterility of the product isnot ensured during transportation;

[0033] when the syringes are delivered with a stopper, an additionalmanipulation is necessary, which exposes both the product and theoperator.

AIM OF THE INVENTION

[0034] The aim of the present invention is to offer a method and adevice for producing, packaging and handling injectable substances ofradiopharmaceutical compounds, preferably in the form of individualpatient-doses of radiopharmaceutical compounds, allowing the exposure ofthe staff, the number of manipulations and the need for accessoryequipment to be reduced to the minimum, while maintaining isolation andsterilization of said compounds from the external environment.

SUMMARY OF THE INVENTION

[0035] The present invention relates to a method for preparing,packaging and handling an individual patient-dose of aradiopharmaceutical compound, in particular for use as a short-livedcompound in PET applications, comprising the following steps:

[0036] filling a cartridge with said dose of radiopharmaceuticalcompound via a first end, the second end being closed by means of acomponent serving as a piston;

[0037] closing said cartridge at said first end by means of a closuredevice;

[0038] placing said cartridge in a radiation shielding device,comprising an inner part and an outer part, said inner part serving asradiation shielding for an operator and said outer part serving as atransportation container;

[0039] closing said container by means of an appropriate shielding lid;

[0040] transporting said container up to the place at which an injectionof said radiopharmaceutical compound will take place;

[0041] removing the shielding lid of the container;

[0042] fixing a plunger to the cartridge piston;

[0043] extracting the cartridge and the inner part of the radiationshielding device from the outer part serving as a container, and

[0044] placing injection means on the cartridge end which has thesetting closure device.

[0045] The cartridge may be a standard cartridge, such as those used forthe packaging of insulin.

[0046] Further, according to the invention, a radiation shielding deviceis provided, comprising an inner cylinder-like part being able tocomprise said cartridge, and an outer cylinder-like part, serving as anadditional shielding for transportation. The inner part is capable to beplaced inside the outer part. The outer part is able to be closed by ashielding lid. The inner cylinder-like part is preferably made of highdensity metal such as tungsten or a tungsten-based alloy. The outercylinder-like part and the shielding lid are preferably made of a highdensity metal such as lead, tungsten, a high lead content alloy or ahigh tungsten content alloy.

[0047] Also, according to the invention, a plunger to be used in themethod is provided, said plunger comprising a sliding rod, a pushbutton, means for fixing said plunger to the inner part of the radiationshielding device and support wings for the fingers.

[0048] Also according to the invention, an injection means to be used inthe method is provided, said injection means comprising a needle or aluer fitting connected to a spike, said spike being capable to piercethe set closure of the cartridge in a sterile manner and to enter incontact with said radiopharmaceutical compound, when said cartridge isinside the cartridge radiation shielding. The spike is protected in asterile manner by an elastomeric sleeve until set closure of cartridgehas been pierced.

BRIEF DESCRIPTION OF THE DRAWINGS

[0049]FIGS. 1a and 1 b represent an open cartridge with its settingstopper and a closed cartridge respectively.

[0050]FIG. 2 represents, in a cutaway view, a radiation-shielding device

[0051]FIGS. 3a, 3 b and 3 c represent a plunger, viewed separately,viewed assembled on the cartridge radiation shielding and viewed duringextraction from the shielding device used for the transportationrespectively.

[0052]FIGS. 4a, 4 b and 4 c represent a first embodiment of injectionmeans comprising a spike and a needle, with and without its sleeve andcaps respectively.

[0053]FIGS. 5a, 5 b and 5 c represent a second embodiment of injectionmeans comprising a spike and a male luer-lock device, with and withoutits cap and plug respectively.

[0054]FIG. 6 is a view of the ready-to-use injection device.

DETAILED DESCRIPTION OF SEVERAL PREFERRED EMBODIMENTS OF THE PRESENTINVENTION

[0055] The present invention is related to a method and devices forpreparing, packaging and handling individual doses of an injectableradiopharmaceutical compound. The method combines and incorporates thefunctions of filling (production) and transportation (packaging) and usewhile at the same time allowing the production to be easily automated.

[0056] The method of the invention comprises the following steps:

[0057] filling a “cartridge” 1 with an injectable substance of aradiopharmaceutical compound (FIG. 1);

[0058] closing said cartridge 1 at one end by means of a settingelastomeric (rubber) stopper 2 to be capable of being pierced, such as aseptum. The cartridge comprises a rubber piston 3 at the other end. Thefilling and closing may be performed automatically using a suitabledispensing device. A cartridge as is known to contain insulin may beused for this purpose;

[0059] placing the cartridge in a radiation shielding device 10consisting of two concentric parts (FIG. 2): a removable inner part 4,called a “cartridge radiation shielding”, consisting of a tube made ofdense material which will also serve as protection for the medical staffduring the injection (thus fulfilling the function of syringe radiationshielding), and an outer part 5 consisting of a “radiation-shieldingcontainer” whose size and thickness are suitable for transportationaccording to the nature of the substance contained in the cartridge. Thecartridge and its shielding can be easily placed in this radiationshielding container by means of an automated device;

[0060] fitting a shielding lid 6 on said container 5;

[0061] transporting said container 5 to the place where the substancewill be administered;

[0062] removing the lid 6 from the transportation container 5 andattaching by clipping or screwing a plunger 7 to the cartridge radiationshielding 4 (FIG. 3);

[0063] extracting the cartridge radiation shielding 4 from thetransportation container 5 by means of this plunger 7. At this stage,the user has in his hands the equivalent of a filled radiation-shieldedsyringe which lacks only the needle

[0064] placing a spike 31 by piercing the elastomeric stopper 2 oppositeto the piston 3. The spike may be a double needle of VACUTAINER® type(from Becton Dickinson) as used for taking blood (FIG. 4) or the spikemay be connected to a male luer fitting (luer-lock or -slipper) adaptedfor any type of subsequent connection of the device. This spike, whichis protected from any dust by an elastomeric (rubber) sleeve 32, isinstalled by piercing the septum 2 of the cartridge 1;

[0065] removing the cap 42 from the intravenous (iv) needle or the plug45 of the luer fitting in order to carry out the injection (FIGS. 4 and5).

[0066] The main components used in the method of the invention aredescribed hereunder. Some of them are existing parts, used here for thepurpose of the invention. Others are specific to the invention.

[0067] The cartridge (FIG. 1) is a type of tube 1 closed at one end bymeans of a rubber piston 3 which can slide inside the tube, and fittedat the other end with a system of closure by setting a rubber stopper(not shown) used as a septum 2 with a crimped aluminium ring.

[0068] The cartridge can be any standard commercially availablesingle-use component such as for example “1.5 ml Cartridge, flint type Iglass” from Forma Vitrum A.G. (Switzerland) or “1.8 ml Cartridge, ref.No. 112” from Nuova Ompi (Italy).

[0069] The cartridge radiation shielding 4 (FIG. 2) is a cylindricalcomponent made of a dense radiation shielding alloy, for example atungsten-based alloy. It is hollow, with its inside diameter adapted tothe cartridge. The thickness of the wall is adapted to the weight andradiation shielding constraints. The cartridge radiation shielding isreusable and may be placed in the transportation radiation shieldingcontainer 5. A window 20 may be provided in the shielding 4 to allow thecartridge to be seen through the lateral face. A conical inlet may beprovided to facilitate the automatic insertion of the cartridge 1. Thecartridge radiation shielding 4 is a purpose-designed and purpose-madecomponent, specifically for this invention.

[0070] The transportation container 5 is a cylinder made of densematerial, preferably lead, intended to protect the environment from theradiation emitted by the contents of the cartridge during thetransportation and storage. The container is fitted with a shielding lid6. The internal dimensions are adapted to those of the cartridgeradiation shielding 4. The thickness of the walls is adapted to thenature and intensity of the radioactive source.

[0071] The plunger 7 (FIG. 3) serves to push the cartridge piston 3during the injection and to extract the cartridge radiation shielding 4from the transportation container 5. It is composed of a sliding rod 22fitted at one end with a push button 23 for the thumb and at the otherend with a back face 24 to enter into contact with the cartridge piston3. The fixed part comprises a system for rapid attachment for example byscrewing or clipping, to the cartridge container described above and isfitted with two support wings 25 for the fingers. This component isreusable. It is a purpose-designed and purpose-made assembly,specifically intended for this use.

[0072] According to a first preferred embodiment, as shown in FIGS. 4a,4 b and 4 c, injection means 30 essentially consist in a devicepresenting a needle 33, such as an iv needle, connected to a spike 31.The spike is designed to be able to pierce the set closure 2 of thecartridge 1 when said cartridge is still inside the cartridge radiationshielding 4.

[0073] Advantageously, said spike is protected by an elastomeric sleeve32 and both spike 31 and needle 33 are covered before use by adequateprotective caps 41 and 42.

[0074] According to another preferred embodiment, as shown in FIGS. 5a,5 b and 5 c, the injection means 30 essentially consist in a devicecomprising a spike 31 as described in the previous embodiment and aluer-lock fitting 34 able to be closed by a plug 45.

[0075] Again, the spike 31 may advantageously be protected by anelastomeric sleeve 32. The spike may also be covered before use by aprotective cap 41.

[0076] The injection means 30 is a device permitting rapid fixing of aneedle or luer lock using a screw pitch (threaded part) or a clip (notshown). The fixing is made to the lower end of the radiation-shielding4. The spike 31 is designed to be able to pierce the set closure 2 ofthe cartridge when the latter is inside the cartridge radiationshielding 4. The opposite end of the injection means is either an ivneedle 33 (FIG. 4) or a male luer-lock fitting 34 (FIG. 5). The directuse of a standard single-use spike/needle of VACUTAINER® type as usedfor taking blood is the most practical (Becton Dickinson, Vacutainerneedle, ref. 36-0213).

[0077] In FIG. 6 is described the manner in which the cartridgeradiation shielding 4 provided with its plunger 7 and internally with acartridge 1 is fitted with the injection means such as the spike/needle30 device described in FIG. 4a. Once the set closure 2 has been piercedby the spike 31, through a lower opening in said shielding 4, theprotective cap 42 only needs to be removed in order to proceed with theinjection.

1. Device to be used in the automated preparation, packaging and furtherhandling of a radiopharmaceutical compound individual dose, comprisingthe following set of elements a cartridge intended to contain saidindividual dose, provided at a first end with a closing element (2) andat a second end by means of a component serving as a piston (3); aradiation-shielding container (10) comprising an inner cylinder-likepart (4) capable to enclose said cartridge (1), and an outercylinder-like part (5), serving as an additional shielding fortransportation, said outer part being capable to enclose said innerpart, said outer part being provided with a shielding lid (6) a plunger(7) to be fitted to the cartridge (1) at the time of an injection, whilesaid cartridge is still inside said inner cylinder-like part (4) of theradiation shielding container (10), provided with a sliding rod (22)capable to contact said piston (3) of the cartridge (1), with a pushbutton (23) and with support wings (25) for the fingers; an injectionmeans (30) to be fitted to the first end of the cartridge (1) at thetime of an injection, while said cartridge is still inside said innercylinder-like part (4) of the radiation shielding container (4),wherein: the plunger is provided with fixing means (24) to said innercylinder-like part (4) of the radiation shielding container (10); theclosing element (2) is a septum, preferably an elastomeric stopper andthe injection means (30) is capable to pierce the closing element (2) ofthe cartridge, (1) in a sterile manner and to enter in contact with saidradiopharmaceutical compound.
 2. Device according to claim 1, whereinthe fixing means (24) of the plunger comprise a rapid attachment devicesuch as screwing or clipping means.
 3. Device according to claim 1,wherein said injection means (30) comprises inwardly a spike (31) andoutwardly a needle (33) or a luer fitting (34) in connection to thespike (31), preferably of the VACUTAINER® type.
 4. Device according toclaim 1, wherein said spike (31) is protected in a sterile manner by anelastomeric sleeve (32) until said closing element (2) of cartridge (1)has been pierced.
 5. Device according to claim 3 or 4, wherein theinjection means elements (30) are covered by a protective cap (41,42)before use.
 6. Device according to claim 1, wherein the injection means(30) are designed for rapid attachment to the cartridge such as screwingor clipping.
 7. Device according to claim 1, wherein said cartridge is astandard cartridge of the type used for the packaging of insulin. 8.Device according to claim 1, wherein it is suitable for using ashort-lived Positron Emission Tomography (PET) compound.
 9. Deviceaccording to claim 1, wherein said inner cylinder-like part (4) is madeof high density metal such as tungsten or a tungsten-based alloy. 10.Device according to claim 1, wherein said outer cylinder-like part (5)and said shielding lid (6) are made of a high density metal such aslead, tungsten, a high lead content alloy or a high tungsten contentalloy.
 11. Device according to claim 1, wherein a see-through window(20) is provided in the shielding (4).
 12. Use of the device, accordingto anyone of claim 1 to 11, for automatically preparing, packaging andhandling an individual dose of a radiopharmaceutical compound,comprising the following steps: filling the cartridge (1) with said doseof radiopharmaceutical compound via its first end, its second endremaining closed by means of the piston (3); closing said cartridge (1)at said first end by means of the closure device (2); placing saidcartridge (1) in the radiation shielding device (10), comprising aninner part (4) and an outer part (5), said inner part serving asradiation shielding for an operator and said outer part serving as atransportation shielding container; closing said shielding container (5)by means of the shielding lid (6); transporting said container up to theplace at which an injection of said radiopharmaceutical compound will becarried out; removing the shielding lid (6) of the container; fixing theplunger (7) to the inner part (4) of the shielding device (10);extracting the inner part (4) of the radiation shielding device (10),enclosing the cartridge, from the outer part (5), and placing injectionmeans (30) on the cartridge end which is provided with the closingelement, (2), said cartridge (1) being still enclosed in the inner part(4) of the shielding device (10).